Skip to main content

Advertisement

SpringerLink
Log in

Occurrence of haemophagocytic lymphohistiocytosis at less than 1 year of age: analysis of 96 patients

  • Original Paper
  • Published:
European Journal of Pediatrics Aims and scope Submit manuscript

    We’re sorry, something doesn't seem to be working properly.

    Please try refreshing the page. If that doesn't work, please contact support so we can address the problem.

Abstract

We analysed data of 96 infants (under 1 year of age) with haemophagocytic lymphohistiocytosis (HLH) from the registry of an HLH study conducted during 1986–2002 in Japan. The cases were classified into five groups. The diagnosis of familial HLH (FHL) as group 1 (n =27) was made with positive family history and/or recent molecular test for perforin and Munc13–4 mutations. Neonatal enterovirus- or herpes simplex virus-associated HLH as group 2a (n =7), Epstein-Barr virus–associated HLH (n =12) as group 2b, adenovirus- or cytomegalovirus-associated HLH as group 3 (n =9) were mostly diagnosed by viral isolation or by the detection of viral genome. Juvenile rheumatoid arthritis-associated macrophage activation syndrome was classified as group 4 (n =4) and the remaining without known triggers as group 5 (n =37). The peak onset age was 1–2 months for group 1, 1–2 weeks for group 2a, 12 months for group 2b, none for group 3, 9 months for group 4 and 2 months for group 5. Future novel diagnostic measures are required to define the precise nature of HLH in group 5. Conclusion:These data may provide useful information for neonatologists/ paediatricians in the differential diagnosis of haemophagocytic lymphohistiocytosis in early infancy.

This is a preview of subscription content, log in via an institution to check access.

Access this article

Log in via an institution

Price excludes VAT (USA)
Tax calculation will be finalised during checkout.

Instant access to the full article PDF.

Institutional subscriptions

Fig. 1

Similar content being viewed by others

Abbreviations

AdV :

adenovirus

CMV :

cytomegalovirus

EBV :

Epstein-Barr virus

EV :

enterovirus

FHL :

familial haemophagocytic lymphohistiocytosis

HLH :

haemophagocytic lymphohistiocytosis

HSV :

herpes simplex virus

JRA-MAS :

juvenile rheumatoid arthritis-associated macrophage activation syndrome

NK :

natural killer

SCT :

stem cell transplantation

XLP :

X-linked lymphoproliferative disease

References

  1. Abzug MJ (2001) Prognosis for neonates with enterovirus hepatitis and coagulopathy. Pediatr Infect Dis J 20: 758–763

    Google Scholar 

  2. Arico M, Janka G, Fischer A, Henter JI, Blanche S, Elinder G, Martinetti M, Rusca MP (1996) Hemophagocytic lymphohistiocytosis: Diagnosis, treatment, and prognostic factors. Report of 122 children from the international registry. Leukaemia 10: 197–203

    Google Scholar 

  3. Arico M, Danesino C, Pende D, Moretta L (2001) Pathogenesis of haemophagocytic lymphohistiocytosis. Br J Haematol 114: 761–769

    Google Scholar 

  4. Arico M, Allen M, Brusa S, Clementi R, Pende D, Maccario R, Moretta L, Danesino C (2002) Haemophagocytic lymphohistiocytosis: proposal of a diagnostic algorithm based on perforin expression. Br J Haematol 119: 180–188

    Article  PubMed  Google Scholar 

  5. Barre V, Marret S, Mendel I, Lesesve JF, Fessard CI (1998) Enterovirus-associated haemophagocytic syndrome in neonate. Acta Paediatr 87: 469–471

    Google Scholar 

  6. Duval M, Fenneteau O, Doireau V, Faye A, Emilie D, Yotnda P, Drapier JC, Schlegel N, Sterkers G, de Baulny HO, Vilmer E (1999) Intermittent hemophagocytic lymphohistiocytosis is a regular feature of lysinuric protein intolerance. J Pediatr 134: 236–239

    CAS  PubMed  Google Scholar 

  7. Feldmann J, Le Deist F, Ouachee-Chardin M, Certain S, Alexander S, Quartier P, Haddad E, Wulffraat N, Casanova JL, Blanche S, Fischer A, de Saint Basile G (2002) Functional consequences of perforin gene mutations in 22 patients with familial haemophagocytic lymphohistiocytosis. Br J Haematol 117: 965–972

    Google Scholar 

  8. Feldmann J, Callebaut I, Raposo G, Certain S, Bacq D, Dumont C, Lambert N, Ouachee-Chardin M, Chedeville G, Tamary H, Minard-Colin V, Vilmer E, Blanche S, Le Deist F, Fischer A, de Saint Basile G (2003) Munc 13–4 is essential for cytolytic granules fusion and is mutated in a form of familial hemophagocytic lymphohistiocytosis (FHL3). Cell 115: 461–473

    Google Scholar 

  9. Grom AA (2003) Macrophage activation syndrome and reactive hemophagocytic lymphohistiocytosis: the same entities? Curr Opin Rheumatol 15: 587–590

    Google Scholar 

  10. Hadchouel M, Prieur AM, Griscelli C (1985) Acute hemorrhagic, hepatic, and neurologic manifestations in juvenile rheumatoid arthritis: possible relationship to drugs or infection. J Pediatr 106: 561–566

    Google Scholar 

  11. Henter JI (2002) Biology and treatment of familial hemophagocytic lymphohistiocytosis: importance of perforin in lymphocyte-mediated cytotoxicity and triggering of apoptosis. Med Pediatr Oncol l38: 305–309

    Google Scholar 

  12. Henter JI, Elinder G, Ost A (1991) Diagnostic guidelines for hemophagocytic lymphohistiocytosis. Semin Oncol 18: 29–33

    CAS  PubMed  Google Scholar 

  13. Hunter JI, Arco M, Agiler RM, Linder G, Favor BE, Filipovich AH, Gadner H, Imashuku S, Janka-Schaub G, Komp D, Ladisch S, Webb D (1997) HLH-94: a treatment protocol for hemophagocytic lymphohistiocytosis. HLH Study Group of the Histiocyte Society. Med Pediatr Oncol 28: 342–347

    Google Scholar 

  14. Ikeda H, Kato M, Matsunaga A, Shimizu Y, Katsuura M, Hayasaka K (1998) Multiple sulphatase deficiency and haemophagocytic syndrome. Eur J Pediatr 157: 553–554

    Article  CAS  PubMed  Google Scholar 

  15. Imashuku S (1997) Differential diagnosis of hemophagocytic syndrome: underlying disorders and selection of the most effective treatment. Int J Hematol 66:135–151

    Google Scholar 

  16. Imashuku S (2000) Advances in the management of hemophagocytic lymphohistiocytosis. Int J Hematol 72: 1-11

    Google Scholar 

  17. Imashuku S (2002) Clinical features and treatment strategies of Epstein-Barr virus-associated hemophagocytic lymphohistiocytosis. Crit Rev Hematol/Oncol 44: 259–272

    Google Scholar 

  18. Imashuku S, Tanaka T, Togari H, Teramura T, An B, Okubo H, Itoh H, Hibi S (2000) Detection of hemophagocytes in blood smears in fatal disseminated neonatal herpes simplex virus infection. Int J Pediatr Hematol/Oncol 6: 425–428

    Google Scholar 

  19. Imashuku S, Hyakuna N, Funabiki T, Ikuta K, Sako M, Iwai A, Fukushima T, Kataoka S, Yabe M, Muramatsu K, Kohdera U, Nakadate H, Kitazawa K, Toyoda Y, Ishii E (2002) Low natural killer activity and central nervous system disease as a high-risk prognostic indicator in young patients with hemophagocytic lymphohistiocytosis. Cancer 94: 3023–3031

    Article  PubMed  Google Scholar 

  20. Janka GE (1983) Familial hemophagocytic lymphohistiocytosis. Eur J Pediatr 140: 221–230

    Google Scholar 

  21. Katano H, Ali MA, Patera AC, Catalfamo M, Jaffe ES, Kimura H, Dale JK, Straus SE, Cohen JI (2003) Chronic active Epstein-Barr virus infection associated with mutations in perforin that impair its maturation. Blood 103: 1244–1252

    Google Scholar 

  22. Kogawa K, Lee SM, Villanueva J, Marmer D, Sumegi J, Filipovich AH (2002) Perforin expression in cytotoxic lymphocytes from patients with hemophagocytic lymphohistiocytosis and their family members. Blood 99: 61–66

    Google Scholar 

  23. Ma X, Okamura A, Yosioka M, Ishiguro N, Kikuta H, Kobayashi K (2001) No mutations of SAP/SH2D1A/DSHP and perforin genes in patients with Epstein-Barr virus-associated hemophagocytic syndrome in Japan. J Med Virol 65: 358–361

    Article  CAS  PubMed  Google Scholar 

  24. Mandel H, Gozal D, Aizin A, Tavori S, Jaffe M (1990) Haemophagocytosis in hereditary fructose intolerance: a diagnostic dilemma. J Inherit Metab Dis 13: 267–269

    Google Scholar 

  25. Ohadi M, Lalloz MR, Sham P, Zhao J, Dearlove AM, Shiach C, Kinsey S, Rhodes M, Layton DM (1999) Localization of a gene for familial hemophagocytic lymphohistiocytosis at chromosome 9q21.3–22 by homozygosity mapping. Am J Hum Genet 64: 165–171

    Google Scholar 

  26. Parizhskaya M, Reyes J, Jaffe R (1999) Hemophagocytic syndrome presenting as acute hepatic failure in two infants: clinical overlap with neonatal hemochromatosis. Pediatr Development Pathol 2: 360–366

    Google Scholar 

  27. Rostasy K, Kolb R, Pohl D, Mueller H, Fels C, Moers AV, Bergmann M, Hanefeld F, Pekrun A, Schulz-Schaeffer W (2004) CNS disease as the main manifestation of hemophagocytic lymphohistiocytosis in two children. Neuropediatrics 35: 45–49

    Google Scholar 

  28. Stepp SE, Dufourcq-Lagelouse R, Le Deist F, Bhawan S, Certain S, Mathew PA, Henter JI, Bennett M, Fischer A, de Saint Basile G, Kumar V (1999) Perforin gene defects in familial hemophagocytic lymphohistiocytosis. Science 286: 1957–1959

    Article  CAS  PubMed  Google Scholar 

  29. Suga N, Takada H, Nomura A, Ohga S, Ishii E, Ihara K, Ohshima K, Hara T (2002) Perforin defects of primary haemophagocytic lymphohistiocytosis in Japan. Br J Haematol 116: 346–349

    Google Scholar 

  30. Ueda I, Morimoto A, Inaba T, Yagi T, Hibi S, Sugimoto T, Sako M, Yanai F, Fukushima T, Nakayama M, Ishii E, Imashuku S (2003) Characteristic perforin gene mutations of haemophagocytic lymphohistiocytosis patients in Japan. Br J Haematol 121: 503–510

    Google Scholar 

  31. Whitley R (2004) Neonatal herpes simplex virus infection. Curr Opin Infect Dis 17: 243–246

    Google Scholar 

  32. Yamamoto K, Ishii E, Sako M, Ohga S, Furuno K, Suzuki N, Ueda I, Imayoshi M, Yamamoto S, Morimoto A, Takada H, Hara T, Imashuku S, Sasazuki T, Yasukawa M.(2004) Identification of novel MUNC13–4 mutations in familial hemophagocytic lymphohistiocytosis and functional analysis of MUNC13–4-deficient cytotoxic T lymphocytes. J Med Genet 41: 763–767

    Google Scholar 

Download references

Acknowledgements

The authors thank the many physicians who referred their patients to the HLH registration centre and who registered their patients in the HLH-94 international protocol study. The excellent secretarial assistance of Yasuko Hashimoto is acknowledged.

Author information

Authors and Affiliations

  1. Division of Paediatrics, Takasago-Seibu Hospital, 1-10-41 Nakasuji, Takasago City, Hyogo Prefecture, Japan

    Shinsaku Imashuku & Tomoko Teramura

  2. Department of Paediatrics, Kyoto Prefectural University of Medicine, Kyoto, Japan

    Ikuyo Ueda, Kanako Mori & Akira Morimoto

  3. Division of Paediatrics, Osaka General Hospital, Osaka, Japan

    Masahiro Sako

  4. Department of Paediatrics, Saga University, Saga, Japan

    Eiichi Ishii

Authors
  1. Shinsaku Imashuku
    View author publications

    You can also search for this author in PubMed Google Scholar

  2. Ikuyo Ueda
    View author publications

    You can also search for this author in PubMed Google Scholar

  3. Tomoko Teramura
    View author publications

    You can also search for this author in PubMed Google Scholar

  4. Kanako Mori
    View author publications

    You can also search for this author in PubMed Google Scholar

  5. Akira Morimoto
    View author publications

    You can also search for this author in PubMed Google Scholar

  6. Masahiro Sako
    View author publications

    You can also search for this author in PubMed Google Scholar

  7. Eiichi Ishii
    View author publications

    You can also search for this author in PubMed Google Scholar

Corresponding author

Correspondence to Shinsaku Imashuku.

Rights and permissions

Reprints and permissions

About this article

Cite this article

Imashuku, S., Ueda, I., Teramura, T. et al. Occurrence of haemophagocytic lymphohistiocytosis at less than 1 year of age: analysis of 96 patients. Eur J Pediatr 164, 315–319 (2005). https://doi.org/10.1007/s00431-005-1636-9

Download citation

  • Received:

  • Revised:

  • Accepted:

  • Published:

  • Issue Date:

  • DOI: https://doi.org/10.1007/s00431-005-1636-9

Keywords

Search

Navigation